Dispersible macromolecule compositions and methods for their preparation and use

ABSTRACT

A process for preparing ultrafine powders of biological macromolecules comprises atomizing liquid solutions of the macromolecules, drying the droplets formed in the atomization step, and collecting the particles which result from drying. By properly controlling each of the atomization, drying, and collection steps, ultrafine dry powder compositions having characteristics particularly suitable for pulmonary delivery for therapeutic and other purposes may be prepared.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 10/403,482,filed Mar. 31, 2003, issued as U.S. Pat. No. 7,138,141, which is acontinuation of U.S. Ser. No. 10/007,868, filed Nov. 9, 2001, issued asU.S. Pat. No. 6,592,904, which is a continuation of U.S. Ser. No.09/498,397, filed Feb. 4, 2000, issued as U.S. Pat. No. 6,423,344, whichis a continuation of U.S. Ser. No. 08/644,681, filed May 8, 1996, issuedas U.S. Pat. No. 6,051,256, which is a continuation-in-part of U.S. Ser.No. 08/423,515, filed Apr. 14, 1995, issued U.S. Pat. No. 6,582,728,which is a continuation-in part of U.S. Ser. No. 08/383,475, filed Feb.1, 1995, now abandoned, which is a continuation-in part of U.S. Ser. No.08/207,472, filed Mar. 7, 1994, now abandoned. The full disclosures ofeach of these applications are herein incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to macromolecule compositionsand methods for their preparation and use. In particular, the presentinvention relates to a method for preparing macromolecule compositionsby spray drying under controlled conditions which preserve proteinpurity and results in good powder dispersibility and other desirablecharacteristics.

Over the years, certain drugs have been sold in compositions suitablefor forming a drug dispersion for oral inhalation (pulmonary delivery)to treat various conditions in humans. Such pulmonary drug deliverycompositions are designed to be delivered by inhalation by the patientof a drug dispersion so that the active drug within the dispersion canreach the lung. It has been found that certain drugs delivered to thelung are readily absorbed through the alveolar region directly intoblood circulation. Pulmonary delivery is particularly promising for thedelivery of macromolecules (proteins, polypeptides, high molecularweight polysaccharides, and nucleic acids) which are difficult todeliver by other routes of administration. Such pulmonary delivery canbe effective both for systemic delivery and for localized delivery totreat diseases of the lungs.

Pulmonary drug delivery can itself be achieved by different approaches,including liquid nebulizers, aerosol-based metered dose inhalers(MDI's), and dry powder dispersion devices. Aerosol-based MDI's arelosing favor because they rely on the use of chlorofluorocarbons(CFC's), which are being banned because of their adverse effect on theozone layer. Dry powder dispersion devices, which do not rely on CFCaerosol technology, are promising for delivering drugs that may bereadily formulated as dry powders. Many otherwise labile macromoleculesmay be stably stored as lyophilized or spray-dried powders by themselvesor in combination with suitable powder carriers.

The ability to deliver pharmaceutical compositions as dry powders,however, is problematic in certain respects. The dosage of manypharmaceutical compositions is often critical, so it is desirable thatdry powder delivery systems be able to accurately, precisely, andreliably deliver the intended amount of drug. Moreover, manypharmaceutical compositions are quite expensive. Thus, the ability toefficiently formulate, process, package, and deliver the dry powderswith a minimal loss of drug is critical. While the permeability ofnatural macromolecules in the lung is well known, the combinedinefficiencies of macromolecule production processes and macromoleculedelivery has limited commercialization of dry macromolecule powders forpulmonary delivery.

A particularly promising approach for the pulmonary delivery of drypowder drugs utilizes a hand-held device with a hand pump for providinga source of pressurized gas. The pressurized gas is abruptly releasedthrough a powder dispersion device, such as a venturi nozzle, and thedispersed powder made available for patient inhalation. Whileadvantageous in many respects, such hand-held devices are problematic ina number of other respects. The particles being delivered are usuallyless than 5 μm in size, making powder handling and dispersion moredifficult than with larger particles. The problems are exacerbated bythe relatively small volumes of pressurized gas, which are availableusing hand-actuated pumps. In particular, venturi dispersion devices areunsuitable for difficult-to-disperse powders when only small volumes ofpressurized gas are available with the handpump. Another requirement forhand-held and other powder delivery devices is efficiency. High deviceefficiency in delivering the drug to the patient with the optimal sizedistribution for pulmonary delivery is essential for a commerciallyviable product. Conventional techniques used to deliver medication donot have the delivery efficiency required for commercialization. Theability to achieve both adequate dispersion and small dispersed volumesis a significant technical challenge that requires that each unit dosageof the powdered composition be readily and reliably dispersible.

Spray drying is a conventional chemical processing unit operation usedto produce dry particulate solids from a variety of liquid and slurrystarting materials. The use of spray drying for the formulation of drypowder pharmaceuticals is known, but has usually been limited to smallmolecule and other stable drugs which are less sensitive to thermaldegradation and other rigorous treatment conditions. The use of spraydrying for the preparation of biological macromolecule compositions,including proteins, polypeptides, high molecular weight polysaccharides,and nucleic acids, can be problematic since such macromolecules areoften labile and subject to degradation when exposed to hightemperatures and other aspects of the spray drying process. Excessivedegradation of the macromolecules can lead to drug formulations lackingin the requisite purity. It can also be difficult to control particlesize and particle size distribution in compositions produced by spraydrying. For pulmonary delivery, it is critical that the average particlesize be maintained below 5 μm, preferably in the range from 0.4 μm to 5μm, and that the amount of the composition comprising particles outsideof the target size range be minimized. Preferably, at least 90% byweight of the powder will have a particle size in the range from 0.1 μmto 7 μm. More preferably, at least 95% will have a size in the rangefrom 0.4 μm to 5μm. Moreover, it can sometimes be difficult to achieve adesired low moisture content required for physical and chemicalstability in the final particulate product, particularly in an economicmanner. Finally, and perhaps most important, it has been difficult toproduce the small particles necessary for pulmonary delivery in anefficient manner. For high value macromolecular drugs, collectionefficiencies (i.e., the amount of particulate drug recovered from theprocess in a useable form) should be above 80% by weight, preferablyabove 90% by weight, and desirably above 95% by weight. While spraydrying has been used to prepare powder of macromolecules in laboratoryscale equipment as described below, commercial spray driers are notdesigned to produce powders in the pulmonary size range. The methods foratomization, drying powder, and collection must be modified toeconomically produce a protein powder with the desired productcharacteristics for pulmonary delivery and in sufficient yield and atcommercially acceptable production rates (in excess of 30 g/hr).

It is therefore desirable to provide improved methods for the spraydrying of macromolecules for use in pulmonary and other drug delivery.In particular, it is desirable to provide improved process methods andpowder composition which address at least some of the deficiencieslisted above.

2. Description of the Related Art

U.S. Pat. Nos. 5,260,306, 4,590,206, GB 2 105 189, and EP 072 046describe a method for spray drying nedocromil sodium to form smallparticles preferably in the range from 2 to 15 μm for pulmonarydelivery. U.S. Pat. No. 5,376,386, describes the preparation ofparticulate polysaccharide carriers for pulmonary drug delivery, wherethe carriers comprise particles sized from 5 to 1000 μm and having arugosity less than 1.75. Mumenthaler et al. (1994) Pharm. Res. 11:12describes recombinant human growth hormone and recombinant tissue-typeplasminogen activator. That study demonstrated that the proteins maydegrade during spray drying and hence may not retain sufficient activityfor therapeutic use. WO 95/23613 describes preparing an inhalationpowder of DNase by spray drying using laboratory-scale equipment. WO91/16882 describes a method for spray drying proteins and other drugs inliposome carriers.

The following applications assigned to the assignee of the presentapplication each describe that spray drying may be used to prepare drypowders of biological macromolecules: application Ser. No. 08/423,515,filed on Apr. 14, 1995, now U.S. Pat. No. 6,582,728; application Ser.No. 08/383,475, now abandoned, which was a continuation-in-part ofapplication Ser. No. 08/207,472, filed on Mar. 7, 1994, now abandoned;application Ser. No. 08/472,563, filed on Apr. 14, 1995, now abandoned,which was a continuation-in-part of application Ser. No. 08/417,507,filed on Apr. 4, 1995, now abandoned, which was a continuation ofapplication Ser. No. 08/044,358, filed on Apr. 7, 1993, now abandoned;application Ser. No. 08/232,849, filed on Apr. 25, 1994, now U.S. Pat.No. 5,607,915, which was a continuation of application Ser. No.07/953,397, now abandoned. WO 94/07514 claims priority from Ser. No.07/953,397. WO 95/24183 claims priority from Ser. Nos. 08/207,472 and08/383,475.

SUMMARY OF THE INVENTION

According to the present invention, methods for spray drying biologicalmacromolecules provide pharmaceutical compositions having improvedcharacteristics which overcome at least some of the deficiencies notedabove with respect to prior spray drying processes. The methods of thepresent, invention comprise providing a predetermined concentration ofthe macromolecule and optionally other excipients as a solution, slurry,suspension, or the like, in a liquid medium, usually in water as anaqueous solution. The macromolecule is optionally formulated in solutionwith compatible excipients such as sugars, buffers, salts, and otherproteins, as needed to provide a therapeutically effective dose, inhibitdegradation during drying, promote powder dispersibility, and achieveacceptable physical and chemical stability of the powder at roomtemperature. The liquid medium is atomized under conditions selected toform droplets having an average particle size at or below apredetermined value, and the droplets are then dried under conditionsselected to form particles of the formulation having a moisture contentbelow a predetermined threshold level. The dried particles are collectedand packaged in a form suitable for use, typically in a unit dosagereceptacle. The conditions of atomizing and drying will preferably beselected so that the particles may be dried below the target moisturecontent in a single drying step, and so that the particles are producedin the desired size range without having to further separate (e.g., sizeclassify) the particles prior to packaging.

In a first preferred aspect of the method of the present invention, thetotal solids content in the liquid medium (including the macromoleculeand excipient(s)) will be below 10% usually being in the range between0.5% and 10% wt. Preferably, the concentration will be in the range fromabout 1% wt to 5% wt, and the liquid medium will comprise an aqueoussolution. It has been found that control of the concentration of thetotal solids below 5% significantly enhances the ability to obtain driedparticles in the desired size range, i.e., below 5 μm, and preferably inthe range from 0.4 μm to 5 μm.

In a second preferred aspect of the method of the present invention, thesolution is atomized to produce droplets having a median droplet size ator below 11 μm. Optimization of the atomizer design and operatingconditions allows the solids content to be increased to the levelsdescribed above making high volume production practical and economical.Preferably, the atomization step is performed by flowing the solutionand an atomization gas stream through a two-fluid nozzle at apredetermined gas:liquid mass flow ratio, preferably above 5. The airpressure upstream of the air orifice is maintained above 25 psig. Whilesuch air pressure is above that which results in sonic velocity, i.e.,the velocity does not continue to increase above sonic velocity, it hasbeen found that increased density of the higher pressure atomization gasdecreases the droplet size produced.

In another aspect of the method of the present invention, the atomizeddroplets are dried to form particles having a final moisture contentbelow 5% by weight. Preferably, the particles are dried to this level ina single drying operation, typically within a single spray dryingoperation where the droplets are flowed concurrently with a heated gasstream having sufficient heat energy to evaporate water in the particlesto the desired level before the particles are collected from the dryingoperation. Usually, the heated gas stream, typically a heated airstream, will have an inlet temperature of at least 90° C., preferablybeing at least 120° C., more preferably being at least 135° C., andstill more preferably being at least 145° C., and often being 175° C.,or as high as 200° C. depending on the macromolecule being dried. Atleast in part, the inlet temperature of the heated gas drying streamwill depend on the lability of the biological macromolecule beingtreated. In the exemplary case of insulin, an inlet temperature in therange from 140° C. to 150° C. is preferred.

In order to control the final moisture content of the particles producedin the drying operation, it is desirable to also control the gas outlettemperature. The gas outlet temperature will be a function of the inlettemperature, the heat load imposed by the product drying step, (whichdepends on the inlet temperature of the liquid medium, the quantity ofwater to be evaporated, and the like), and other factors. Preferably,the gas outlet temperature will be maintained at at least 50° C. orabove, preferably at at least 70° C., usually being in the range from60° C. to 80° C.

In yet another specific aspect of the method of the present invention,the drying conditions will be selected to control the particlemorphology in order to enhance powder dispersibility. In particular, thedrying conditions are selected to provide particles having a rugosity ofat least 2. Rugosity is a measure of surface convolution, with a highernumber indicating a higher degree of surface irregularity. Withoutintending to limit the scope of the present invention in any way, it ispresently believed that the increase in surface irregularity as measuredby rugosity results in a decrease in cohesiveness between adjacentparticles. Such decrease in surface interactions, in turn, improves thedispersibility of the resulting powders. Particle rugosity is influencedby both the drying rate of the individual droplets and the compositionof the dissolved solids.

Droplets are initially dried at a relatively high rate which will createa viscous layer of material about the exterior of the liquid droplet. Asthe drying continues, the viscous layer is unable to flow as rapidly asthe shrinking of the particle as the solvent evaporates, resulting insurface convolutions (wrinkling) of the particles. The viscosity of theviscous layer has been related to the glass transition temperature ofthe material by the WLF equation (Williams, Landel, Ferry Equation) ref.K. Alexander & C. J. King, Drying Technology, Vol. 3, No. 3, 1985. Thetemperature gradient within the drying zone should be controlled so thatthe particle drying occurs sufficiently rapidly to result in the surfacecollapse and convolution without preceding so rapidly that the particlefractures.

In still another specific aspect of the method of the present invention,the dried particles are collected by separating substantially the entireparticle output of the drying step from the gas stream. It has beenfound that proper control of the atomization and drying conditions canproduce a dried powder having at least 90% of the mass of particles inthe size range from 0.1 μm to 7 μm, more preferably having at least 95%in the size range from 0.4 μm to 5 μm, thus permitting the output of thedrying step to be collected and the powder used without the need to sizeclassify the product prior to packaging. The collected powder may thenbe used in any conventional manner for powder pharmaceuticals. Usually,a portion of the particle output will be packaged in a suitablecontainer, such as a unit dosage container useful in dry powderinhalers.

In yet another specific aspect of the method of the present invention,the powder separation step will comprise passing the entire gas streamthrough a separator, where the separator removes at least about 90% byweight of all particles having the size of 1 μm from the gas stream. Theseparator may comprise a high efficiency cyclone specifically designedand operated under conditions resulting in the requisite high removalefficiency for the ultrafine particles produced by the method of thepresent invention. Alternatively, the separator may comprise filterelements, such as a sintered metal fiber filter, a membrane filter,(e.g, a bag filter), or the like.

The methods of the present invention are useful for producing drypowders of biological macromolecules, typically macromolecules which aresuitable for pharmaceutical uses, i.e., as drugs for human andveterinary purposes. Biological macromolecules include proteins,polypeptides, oligopeptides, high molecular weight polysaccharides(typically having a molecular weight above 2 kD), nucleic acids, and thelike. Particular biological macromolecules are set forth in Table 1below. The method is particularly useful for producing dry powders ofinsulin, which is a polypeptide hormone having a molecular weight ofabout 7.5 kD or above. Insulin powders prepared according to the presentinvention may be derived from animal sources, such as bovine insulin, ormay be prepared recombinantly. Recombinant insulins may have an aminoacid sequence identical to that of natural human insulin, or may bemodified to some extent while maintaining the desired insulin activity.

Compositions according to the present invention comprise dispersiblemacromolecule powders intended for pulmonary delivery, i.e., inhalationby a patient into the alveolar regions of the patient's lungs. Thecompositions comprises particles having an average particle size below10 μm and a rugosity above 2, preferably being above 3, and sometimesbeing above 5, usually being in the range from 2-6, preferably being inthe range from 3-6, and sometimes being in the range from 4-6.Preferably, the particles of the composition will have a moisturecontent below 5% by weight, more preferably below 3% by weight, andtypically below 2% by weight. Rugosity may be measured by BET or otherconventional particle surface analysis techniques. Preferably, 90% byweight of the compositions will comprise particles having a particlesize in the range from 0.1 μm to 7 μm, more preferably 95% in the rangefrom 0.4 μm to 5 μm. The compositions will often be packaged as unitdoses where a therapeutically effective amount of the composition ispresent in a unit dose receptacle, such as a blister pack, gelatincapsule, or the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating the primary unit operations ofthe methods of the present invention.

FIG. 2 is a more detailed flowchart illustrating a system suitable forperforming an exemplary method according to the present invention

FIG. 3 is a schematic illustration depicting a preferred atomizationnozzle useful for performing the atomization step of the method of thepresent invention.

FIG. 4 illustrates alternative apparatus for the system of FIG. 2 forperforming the separation step of the method of the present invention.

DETAILED DESCRIPTION

The present invention relates to the methods for preparing compositionscomprising ultrafine dry powder of biological macromolecules intendedprimarily for pulmonary delivery to patients for a variety oftherapeutic and clinical purposes where a first primary aspect of theinvention relates to control of powder characteristics which enhance useof the powders for the intended purposes. A second primary aspect of thepresent invention relates to the compositions themselves as well aspackaged compositions, particularly including unit dosage forms of thecompositions. A third primary aspect of the present invention relates tothe capacity of the demonstrated process to produce powders with thedesired characteristics at a scale that can support market requirementsof a given drug.

The term “biological macromolecule” is intended to include known andfuture biological compounds having therapeutic and other usefulactivities. The biological macromolecules will typically be proteins,polypeptides, oligopeptides, nucleic acids, and relatively high weightpolysaccharides, and the methods of the present invention can reformsuch compounds into ultrafine dry powders having desirablecharacteristics, particularly for pulmonary delivery. Some examples ofbiological macromolecules suitable for preparation as ultrafine drypowders according to the method of the present invention are set forthin Table 1 below. Such biological macromolecules will initially besolubilized, suspended, or otherwise dispersed in an evaporable liquidmedium which is then atomized, dried, and collected according to themethod of the present invention. Preferred biological macromoleculesinclude insulin, interleukin-1 receptor, parathyroid hormone (PTH-34),alpha-1 antitrypsin, calcitonin, low molecular weight heparin, heparin,interferon, and nucleic acids. A detailed example for the preparation ofinsulin compositions using the methods of the present invention is setforth in the Experimental section below.

TABLE 1 EXEMPLARY BIOLOGICAL MACROMOLECULE DRUGS DRUG INDICATIONSCalcitonin Osteoporosis Prophylaxis Paget's Disease HypercalcemiaErythropoietin (EPO) Anemia Factor IX Hemophilia B Granulocyte ColonyNeutropenia Stimulating Factor (G-CSF) Granulocyte Macrophage BoneMarrow Engraftment/ Colony Stimulating Factor Transplant Failure(GM-CSF) Growth Hormone Short Stature Renal Failure Heparin BloodClotting Asthma Heparin (Low Molecular Blood Clotting Weight) InsulinType I and Type II Diabetes Interferon Alpha Hepatitis B and C HairyCell Leukemia Kaposi's Sarcoma Interferon Beta Multiple SclerosisInterferon Gamma Chronic Granulomatous Disease Interleukin-2 RenalCancer Luteinizing Hormone Prostate Cancer Releasing EndometriosisHormone (LHRH) Somatostatin Analog Gastrointestinal Cancers VasopressinAnalog Diabetes Insipidus Bed Wetting Follicle Stimulating FertilityHormone (FSH) Amylin Type I Diabetes Ciliary Neurotrophic Lou Gehrig'sDisease Factor Growth Hormone Short Stature Releasing Factor (GRF)Insulin-Like Growth Osteoporosis Factor Nutritional SupportInsulinotropin Type II Diabetes Interferon Beta Hepatitis B and CInterferon Gamma Rheumatoid Arthritis Interleukin-1 Receptor RheumatoidArthritis Antagonist Interleukin-3 Adjuvant to ChemotherapyInterleukin-4 Immunodeficiency Disease Interleukin-6 ThrombocytopeniaMacrophage Colony Fungal Disease Stimulating Cancer Factor (M-CSF)Hypercholesterolemia Nerve Growth Factor Peripheral NeuropathiesParathyroid Hormone Osteoporosis Somatostatin Analog RefractoryDiarrheas Thymosin Alpha 1 Hepatitis B and C IIb/IIIa Inhibitor UnstableAngina Alpha-1 Antitrypsin Cystic Fibrosis Anti-RSV Antibody RespiratorySyncytial Virus Cystic Fibrosis Cystic Fibrosis Transmembrane Regulator(CFTR) Gene Deoxyribonuclease (DNase) Chronic BronchitisBactericidal/Permeability Adult Respiratory Distress Increasing Protein(BPI) Syndrome (ARDS) Anti-CMV Antibody Cytomegalovirus Interleukin-1Receptor Asthma Interleukin-1 Receptor Asthma Antagonist

The phrase “ultrafine dry powder” means a powder composition comprisinga plurality of discrete, dry particles having the characteristics setforth below. In particular, the dry particles will have an averageparticle size below 5 μm, more preferably being in the range from 0.4-5μm, preferably from 0.4-4 μm, and most preferably from 0.4-3 μm. Theaverage particle size of the powder will be measured as mass meandiameter (MMD) by conventional techniques. A particular powder sizingtechnique uses a centrifugal sedimentary particle size analyzer (HoribaCapa 700). The powders will be capable of being readily dispersed in aninhalation device and subsequently inhaled by a patient so that theparticles are able to penetrate into the alveolar regions of the lungs.

Of particular importance to the present invention, the ultrafine dryparticle compositions produced by the method will have particle sizedistributions which enable them to target the alveolar region of thelung for pulmonary delivery of systemically acting proteins. Suchcompositions advantageously may be incorporated into unit dosage andother forms without further size classification. Usually, the ultrafinedry powders will have a size distribution where at least 90% of thepowder by weight will comprise particles having an average size in therange from 0.1 μm to 7μm, with preferably at least 95% being in therange from 0.4 μm to 5 μm. Additionally, it is desirable that theparticle size distribution avoid having an excess amount of particleswith very small average diameters, i.e., below 0.4 μm.

Conversely, known powders of therapeutic compounds that are inhaled forthe treatment of asthma and chronic bronchitis need to be delivered morecentrally in the airways (i.e., not to the alveolar regions). Thesepowders can produce an aerosol with a significantly larger particle sizedistribution having a mean diameter between 3 and 10 μm. Powders of thissize are collected more readily in high yield in conventional spraydriers, than the powders having the optimal particle size for pulmonarydelivery.

The term “dry” means that the particles of the powder have a moisturecontent such that the powder is physically and chemically stable instorage at room temperature and is readily dispersible in an inhalationdevice to form an aerosol. Usually, the moisture content of theparticles is below 10% by weight water, usually being below 5% byweight, preferably being below 3% by weight, more preferably being below2% by weight, and optionally being below about 1% by weight or lower.The moisture content will usually be controlled by the dryingconditions, as described in more detail below.

The term “dry” means that the particles of the powder have a moisturecontent such that the powder is readily dispersible in an inhalationdevice to form an aerosol. Usually, the moisture content of theparticles is below 10% by weight water, usually being below 5% byweight, preferably being below 3% by weight, more preferably being below2% by weight, and optionally being below about 1% by weight or lower.The moisture content will usually be controlled by the dryingconditions, as described in more detail below. In some cases, however,non-aqueous medium may be used for dispersing the biologicalmacromolecules, in which case the aqueous content may approach zero.

The term “therapeutically effective amount” is the amount present in thecomposition that is needed to provide the desired level of drug in thesubject to be treated to give the anticipated physiological response.This amount is determined for each drug on a case-by-case basis. Theterm “physiologically effective amount” is that amount delivered to asubject to give the desired palliative or curative effect. This amountis specific for each drug and its ultimate approved dosage level.

The therapeutically effective amount of active pharmaceutical will varyin the composition depending on the biological activity of thebiological macromolecule employed and the amount needed in a unit dosageform. Because the subject powders are dispersible, it is highlypreferred that they be manufactured in a unit dosage form in a mannerthat allows for ready manipulation by the formulator and by theconsumer. This generally means that a unit dosage will be between about0.5 mg and 15 mg of total material in the dry powder composition,preferably between about 2 mg and 10 mg. Generally, the amount ofmacromolecule in the composition will vary from about 0.05% w to about99.0% w. Most preferably the composition will be about 0.2% to about97.0% w macromolecule.

A pharmaceutically acceptable carrier may optionally be incorporatedinto the particles (or as a bulk carrier for the particles) to providethe stability, dispersibility, consistency and/or bulkingcharacteristics to enhance uniform pulmonary delivery of the compositionto a subject in need thereof. The term “pharmaceutically acceptablecarrier” means that the carrier can be taken into the lungs with nosignificant adverse toxicological effects on the lungs. Numerically theamount may be from about 0.05% w to about 99.95% w, depending on theactivity of the drug being employed. Preferably about 5% w to about 95%w will be used.

Such pharmaceutically acceptable carriers may be one or a combination oftwo or more pharmaceutical excipients, but will generally besubstantially free of any “penetration enhancers.” Penetration enhancersare surface active compounds which promote penetration of a drug througha mucosal membrane or lining and are proposed for use in intranasal,intrarectal, and intravaginal drug formulations. Exemplary penetrationenhancers include bile salts, e.g., taurocholate, glycocholate, anddeoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatibledetergents, e.g., Tweens, Laureth-9, and the like. The use ofpenetration enhancers in formulations for the lungs, however, isgenerally undesirable because the epithelial blood barrier in the lungcan be adversely affected by such surface active compounds. The drypowder compositions of the present invention are readily absorbed in thelungs without the need to employ penetration enhancers.

The types of pharmaceutical excipients that are useful as carriers inthis invention include stabilizers such as human serum albumin (HSA),bulking agents such as carbohydrates, amino acids and polypeptides; pHadjusters or buffers; salts such as sodium chloride; and the like. Thesecarriers may be in a crystalline or amorphous form or may be a mixtureof the two.

It has been found that HSA is particularly valuable as a carrier in thatit provides improved dispersibility.

Bulking agents which may be combined with the powders of the presentinvention include compatible carbohydrates, polypeptides, amino acids orcombinations thereof. Suitable carbohydrates include monosaccharidessuch as galactose, D-mannose, sorbose, and the like; disaccharides, suchas lactose, trehalose, and the like; cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose,maltodextrins, dextrans, and the like; alditols, such as mannitol,xylitol, and the like. A preferred group of carbohydrates includeslactose, trehalose, raffinose maltodextrins, and mannitol. Suitablepolypeptides include aspartame. Amino acids include alanine and glycine,with glycine being preferred.

Additives, which are minor components of the composition of thisinvention, may be included for conformational stability during spraydrying and for improving dispersibility of the powder. These additivesinclude hydrophobic amino acids such as tryptophan, tyrosine, leucine,phenylalanine, and the like.

Suitable pH adjusters or buffers include organic salts prepared fromorganic acids and bases, such as sodium citrate, sodium ascorbate, andthe like; sodium citrate is preferred.

The methods of the present invention have been found to provideparticles which are dispersible and which further resist agglomerationand undesirable compaction during handling and packaging operations. Aparticular characteristic which has been found to relate directly tosuch improved dispersibility and handling characteristics is the productrugosity. Rugosity is the ratio of the specific area (as measured byBET, molecular surface adsorption, or other conventional technique) andthe surface area calculated from the particle size distribution (asmeasured by centrifugal sedimentary particle size analyzer, Horiba Capa700) and particle density (as measured by pycnometry), assumingnon-porous spherical particles. If the particles are known to begenerally nodular in shape, as is the case in spray drying, rugosity isa measure of the degree of convolution or folding of the surface. Thismay be verified for powders made by the present invention by SEManalysis. A rugosity of 1 indicates that the particle surface isspherical and non-porous. Rugosity values greater than 1 indicate thatthe particle surface is non-uniform and convoluted to at least someextent, with higher numbers indicating a higher degree ofnon-uniformity. For the powders of the present invention, it has beenfound that particles preferably have a rugosity of at least 2, morepreferably being at least 3, usually being in the range from 2-6,preferably being in the range from 3-6, and more preferably being in therange from 4-6.

Unit dosage forms for pulmonary delivery of dispersible dry powderbiological macromolecules comprise a unit dosage receptacle containing adry powder as described above. The powder is placed within a suitabledosage receptacle in an amount sufficient to provide a subject with drugfor a unit dosage treatment. The dosage receptacle is one that fitswithin a suitable inhalation device to allow for the aerosolization ofthe dry powder composition by dispersion into a gas stream to form anaerosol and then capturing the aerosol so produced in a chamber having amouthpiece attached for subsequent inhalation by a subject in need oftreatment. Such a dosage receptacle includes any container enclosing thecomposition known in the art such as gelatin or plastic capsules with aremovable portion that allows a stream of gas (e.g., air) to be directedinto the container to disperse the dry powder composition. Suchcontainers are exemplified by those shown in U.S. Pat. No. 4,227,522issued Oct. 14, 1980; U.S. Pat. No. 4,192,309 issued Mar. 11, 1980; andU.S. Pat. No. 4,105,027 issued Aug. 8, 1978. Suitable containers alsoinclude those used in conjunction with Glaxo's Ventolin Rotohaler brandpowder inhaler or Fison's Spinhaler brand powder inhaler. Anothersuitable unit-dose container which provides a superior moisture barrieris formed from an aluminum foil plastic laminate. Thepharmaceutical-based powder is filled by weight or by volume into thedepression in the formable foil and hermetically sealed with a coveringfoil-plastic laminate. Such a container for use with a powder inhalationdevice is described in U.S. Pat. No. 4,778,054 and is used with Glaxo'sDiskhaler® (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237).Preferred dry powder inhalers are those described in U.S. patentapplication Ser. No. 08/309,691, now U.S. Pat. No. 5,785,049, and Ser.No. 08/487,184, now U.S. Pat. No. 5,740,794, assigned to the assignee ofthe present invention. The latter application has been published as WO96/09085.

Referring now to FIG. 1, processes according to the present inventionfor preparing dispersible dry powders of biological macromoleculescomprise an atomization operation 10 which produces droplets of a liquidmedium which are dried in a drying operation 20. Drying of the liquiddroplets results in formation of the discrete particles which form thedry powder compositions which are then collected in a separationoperation 30. Each of these unit operations will be described in greaterdetail below.

The atomization process 10 may utilize any one of several conventionalforms of atomizers. The atomization process increases the surface areaof the starting liquid. This requires an increase in the surface energyof the liquid, the magnitude of which is directly proportional to thearea increase, which in turn, is inversely proportional to the square ofthe diameter of the droplets. The source of this energy increase dependson the type of atomizer used. Any atomizer (centrifugal, sonic,pressure, two fluid) capable of producing droplets with a mass mediandiameter of less than about 11 μm could be used. Preferred for thepresent invention is the use of two fluid atomizers where the liquidmedium is delivered through a nozzle concurrently with a high pressuregas stream. Particularly preferred is the use of two-fluid atomizationnozzles as described in more detail below which is capable of producingdroplets having a median diameter less than 10 μm.

The atomization gas will usually be air which has been filtered orotherwise cleaned to remove particulates and other contaminants.Alternatively, other gases, such as nitrogen may be used. Theatomization gas will be pressurized for delivery through the atomizationnozzle, typically to a pressure above 25 psig, preferably being above 50psig. Although flow of the atomization gas is generally limited to sonicvelocity, the higher delivery pressures result in an increasedatomization gas density. Such increased gas density has been found toreduce the droplet size formed in the atomization operation. Smallerdroplet sizes, in turn, result in smaller particle sizes. Theatomization conditions, including atomization gas flow rate, atomizationgas pressure, liquid flow rate, and the like, will be controlled toproduce liquid droplets having an average diameter below 11 μm asmeasured by phase doppler velocimetry. In defining the preferredatomizer design and operating conditions, the droplet size distributionof the liquid spray is measured directly using Aerometric's PhaseDoppler Particle Size Analyzer. The droplet size distribution may alsobe calculated from the measured dry particle size distribution (HoribaCapa 700) and particle density. The results of these two methods are ingood agreement with one another. Preferably, the atomized droplets willhave an average diameter in the range from 5 μm to 11 μm, morepreferably from 6 μm to 8 μm. The gas:liquid mass flow ratio ispreferably maintained above 5, more preferably being in the range from 8to 10. Control of the gas:liquid mass flow ratio within these ranges isparticularly important for control of the particle droplet size.

Heretofore, it had been generally thought that conventional atomizationequipment for spray driers was not suitable for producing the very finedroplets (>11 μm) used in the present invention. See, e.g. Masters,Handbook of Spray Drying, 4th ed., Wiley & Sons 1985. It has been found,however, that operation of two fluid nozzles within the parameters setforth above can reliably achieve spray droplets in the desired sizerange.

The liquid medium may be a solution, suspension, or other dispersion ofthe biological macromolecule in a suitable liquid carrier. Preferably,the biological macromolecule will be present as a solution in the liquidsolvent in combination with the pharmaceutically acceptable, and theliquid carrier will be water. It is possible, however, to employ otherliquid solvents, such as organic liquids, ethanol, and the like. Thetotal dissolved solids (including the macromolecule and other carriers,excipients, etc., that may be present in the final dried particle) maybe present at a wide range of concentrations, typically being present atfrom 0.1% by weight to 10% by weight. Usually, however, it will bedesirable to maximize the solids concentration that produces particlesin the inhalation size range and has the desired dispersibilitycharacteristics, typically the solids concentration ranges from 0.5% to10%, preferably from 1.0% to 5%. Liquid media containing relatively lowconcentrations of the biological macromolecule will result in driedparticulates having relatively small diameters as described in moredetail below.

The drying operation 20 will be performed next to evaporate liquid fromthe droplets produced by the atomization operation 10. Usually, thedrying will require introducing energy to the droplets, typically bymixing the droplets with a heated gas which causes evaporation of thewater or other liquid medium. Preferably, the mixing is done in a spraydryer or equivalent chamber where a heated gas stream has beenintroduced. Preferably, the heated gas stream will flow concurrentlywith the atomized liquid, but it would also be possible to employcounter-current flow, cross-current flow, or other flow patterns.

The drying operation is controlled to provide dried particles havingparticular characteristics, such as a rugosity above 2, as discussedabove. Rugosities above 2 may be obtained by controlling the drying rateso that a viscous layer of material is rapidly formed on the exterior ofthe droplet. Thereafter, the drying rate should be sufficiently rapid sothat the moisture is removed through the exterior layer of material,resulting in collapse and convolution of the outer layer to provide ahighly irregular outer surface. The drying should not be so rapid,however, that the outer layer of material is ruptured. The drying ratemay be controlled based on a number of variables, including the dropletsize distribution, the inlet temperature of the gas stream, the outlettemperature of the gas stream, the inlet temperature of the liquiddroplets, and the manner in which the atomized spray and hot drying gasare mixed. Preferably, the drying gas stream will have an inlettemperature of at least 90° C., more preferably being within the rangesset forth above. The outlet temperature will usually be at least about70° C., preferably in the ranges set forth above. The drying gas willusually be air which has been filtered or otherwise treated to removeparticulates and other contaminants. The air will be moved through thesystem using conventional blowers or compressors.

The separation operation 30 will be selected in order to achieve veryhigh efficiency collection of the ultrafine particles produced by thedrying operation 20. Conventional separation operations may be used,although in some cases they should be modified in order to assurecollection of sub-micron particles. In an exemplary embodiment,separation is achieved using a filter medium such as a membrane medium(bag filter), a sintered metal fiber filter, or the like. Alternatively,and often preferably, separation may be achieved using cycloneseparators, although it is usually desirable to provide for high energyseparation in order to assure the efficient collection of sub-micronparticles. The separation operation should achieve collection of atleast 80% of all particles above 1 μm in average particle size,preferably being above 85%, more preferably being above 90%, and evenmore preferably being above 95%, in collection efficiency.

In some cases, a cyclone separator can be used to separate very fineparticles, e.g. 0.1 μm, from the final collected particles. The cycloneoperating parameters can be selected to provide an approximate cutoffwhere particles above about 0.1 μm are collected while particles below0.1 μm are carried over in the overhead exhaust. The presence ofparticles below 0.1 μm in the pulmonary powder is undesirable since theywill generally not deposit in the alveolar regions of the lungs, butinstead will be exhaled.

A particular advantage of the method of the present invention is thatall of the particles produced in the drying operation and collected inthe separation operation may be used for packaging in the desiredpharmaceutical packages without the need to further separate or classifythe particles into desired size ranges. This result is a combination ofthe atomization and drying conditions which produce an ultrafine drypowder composition having individual particles sized within the rangesdesirable for pulmonary delivery. Thus, the separation operation 30 needonly separate the particles from the drying gas stream (with an optional0.4 μm cutoff), where separation is achieved at as high an efficiency aspossible since substantially all of the collected material is suitablefor use in the pharmaceutical formulations.

Referring now to FIG. 2, an exemplary process flow diagram forperforming the method of the present invention will be described. Theprocess flow diagram includes a spray dryer 50, which may be acommercial spray dryer (adapted for the method of the present invention)such as those available from suppliers such as Buchi, Niro, APV, YamatoChemical Company, Okawara Kakoki Company, and others. The spray dryer isfed a solution of the liquid medium (solution feed) described abovethrough a supply pump 52, filter 54, and supply line 56. The supply line56 is connected to a two-fluid atomization nozzle 57, as described belowin connection with FIG. 3. Atomizing air is supplied from a compressor58, a filter 60, and line 62 to the nozzle 57. Drying air is alsoprovided to the spray dryer 50 through a heater 65 and a filter 66.

Dried particles from the spray dryer 50 are carried by the air flowthrough conduit 70 to a filter housing 72. The filter housing 72includes a plurality of internal filter elements 74, which may be bagfilters or sintered metal fiber filters, such as sintered stainlesssteel fiber filters of the type described in Smale, ManufacturingChemist, p. 29, April 1992. Alternative filter media comprise bagfilters, cloth filters, and cartridge filters. In all cases, the gasstream carrying the dried particles will flow into the shell ofseparator housing 72, and the carrier gas will pass through the filterelements 74. Passage of the dried particles, however, will be blocked bythe filter elements, and the dried particles will fall by gravity to thebottom of the housing 72 where they will be collected in a particlecollection canister 76. The canister 76 may periodically be removed andreplaced, and the dry powder in the canister utilized for packaging inunit dosage or other forms. The carrier gas will pass out from the topof the separator housing 72 through line 80 and an exhaust fan 84. Thefilters 82 will collect any particles which may inadvertently passthrough the filter media 74. A source 90 of high pressure gas isprovided for periodically producing a pulsed flow of counter-current airthrough the filter media 74. Such pulsed air flow in the reversedirection will dislodge particles which adhere to the inlet side of thefilter medium to prevent caking. An exemplary system for the productionof an insulin powder according to the method of the present inventionand employing a process flow according to FIG. 2 is presented in theExperimental section below.

Referring now to FIG. 3, an exemplary two-fluid nozzle is illustrated.Flow line 56 includes an inner conduit 100 and outer conduit 102. Theinner conduit 100 carries the solution feed and terminates in an orifice104 having a diameter in the range from 0.015 in. to 0.075 in.,preferably from 0.025 to 0.05 in. depending on the liquid flow rate. Theouter conduit 102 is disposed coaxially about the inner conduit 100 andcarries the atomizing gas from line 62. Conduit 62 terminates in anorifice 110 which is concentric about the orifice 104 of conduit 100.The diameter of orifice 110 is typically larger than that of orifice104, usually having a cross-sectional area which is sufficient toproduce the desired mass flow rate of air with the desired upstreampressure.

Optionally, a cooling jacket 120 may be provided about the spray nozzle(or between the atomizing gas and the solution feed) to maintain arelatively low temperature of the solution feed when the solution feedenters the spray dryer 50. The cooling jacket 120 will typically carrycooling water at a temperature and in an amount sufficient to maintainthe solution feed temperature below a level at which the biologicalmacromolecule might be degraded, usually from 4° C. to 45° C. Coolingwill generally be necessary only with heat sensitive macromolecules.Higher solution feed temperatures result in lower viscosity, where thelower viscosity can reduce the droplet size which is formed by theatomization operation.

Referring now to FIG. 4, as an alternative to use of a filter separator72, as illustrated in FIG. 2, the collection operation may be performedby a cyclone 150. The cyclone 150 will receive the dried particlesthrough conduit 70 and the carrier gas will pass upwardly through line80, in a manner analogous to that illustrated in FIG. 2. The cyclone 150will be designed and operated in a manner to assure very high collectionefficiencies of the ultrafine particles produced by the method of thepresent invention. The use of a cyclone will result in some carry overof extremely fine particles through the overhead outlet 80. While insome cases this may be undesirable, the further separation may be reliedon to remove particles which are too small to reach the alveolar regionsof the lung, e.g. below 7 μm.

The following examples are offered by way of illustration, not by way oflimitation.

EXPERIMENTAL Example 1

The spray drying equipment configuration is shown in FIGS. 2 and 4. Atotal of 20 liters of solution was processed during the run. Thesolution contained 250 grams (1.25% wt.) of total solids, 20% of whichwas insulin. The balance of the solids was a mixture of mannitol, sodiumcitrate and glycine. The solution was fed to the atomizer at 4° C. at arate of about 44 ml/min using a Watson Marlow peristaltic pump andsilicone tubing. The actual feed rate was controlled by a PID loop usingthe spray dryer outlet temperature as the control variable. The atomizertemperature control circulation jacket had 4° C. water circulatedthrough it. The atomizer air was flow controlled and measured using aneedle valve and glass rotameter at 12 scfm and 38 psig. Both the airand liquid flows passed through polishing filters just prior to enteringthe atomizer (Millipak 60 and Millipore Wafergard II F-40 In line gasfilters). The powder was collected in a high efficiency cyclone operatedat a pressure drop of 55 inches H2O. The drying air flow rate wascontrolled by an AC speed control system on the blower drive motor at100 scfm and was measured at the discharge of the blower using anorifice plate and differential pressure transducer. The drying airtemperature was controlled at 130° C. on a time proportioning PID loopand the 7.5 KW heater. A total of 225 grams of powder was recovered infour separate collectors giving a total yield of 90%. The powder in eachcollector was analyzed as shown in Table 2.

TABLE 2 Attribute/Method Units Collector 1 Collector 2 Collector 3Collector 4 Moisture/Karl Fisher H₂O % wt. 3.4%  2.8% 2.8% 3.0% Particlesize/Horiba MMD 1.8 μm 1.4 μm 1.6 μm 1.4 μm Capa 700 % < 5 micron 100100 100 100 Aerosol particle size/ MMAD 3.3 μm ND ND ND Cascade impactor68% Delivered Dose Efficiency % ± SD 83 ± 3 84 ± 5 84 ± 4 81 ± 6 Inhaledevice/gravimetric Surface Area m²/g 11.3 11.7 ND ND Rugosity 3.8 3.9 NDND

Example 2

A total of 2.4 liters of solution was processed. The solution contained100 grams (4.0% wt.) of total solids, 20% of which was insulin. Thebalance of the solids was a mixture of mannitol, sodium citrate andglycine. The spray dryer used in Experiment 1 was used for thisexperiment. The solution was fed to the atomizer at 4° C. at a ratevarying with outlet temperature using a Watson Marlow peristaltic pumpand silicone tubing. The actual feed rate was controlled by a PID loopusing the spray dryer outlet temperature as the control variable. Theatomizer temperature control circulation jacket had 45° C. watercirculated through it. The atomizer air was flow controlled and measuredusing a needle valve and glass rotameter at 13.8 scfm and 70 psig. Bothair and liquid flows passed through polishing filters just prior toentering the atomizer (Millipak 60 and Millipore Wafergard II F-40 Inline gas filters). The drying air flow rate was controlled by an ACspeed control system on the blower drive motor at 95 scfm and wasmeasured at the discharge of the blower using an orifice plate anddifferential pressure transducer. The drying air temperature wascontrolled at 150° C. on a time proportioning PID loop and the 7.5 KWheater. Drying outlet air was varied from 70, 75, and 80° C. The powdercollectors were exchanged for each temperature setpoint. The powder ineach collector was analyzed as shown in Table 3.

TABLE 3 Collector 1 Inlet Collector 2 Inlet Collector 3 InletAttribute/Method Units Air 70° C. Air 75° C. Air 80° C. Moisture KarlFisher H₂O % wt. 2.28 2.02 1.63 Particle size, MMD 2.41 μm 2.69 μm 2.43μm Horiba Capa 700 % < 5 micron 100 82.3 100 Delivered Dose Eff.   % ±SD 71 ± 3 73 ± 3 71 ± 2 Mean Surface Area Micrometrics Gemini m²/g ± SD6.76 ± .19   6 ± .02 8.07 ± .12 Rugosity 3.6 3.9 3.8

Example 3

The spray dryer was reconfigured with a bag house outfitted withsintered stainless steel fiber filter elements (Fairey Microfiltrex).The equipment configuration is shown in FIG. 2.

A total of 8 liters of solution was processed during the insulin run.The solution contained 100 grams (1.25% wt.) of total solids, 20% ofwhich was insulin. The balance of the solids was a mixture of mannitol,sodium citrate and glycine. The solution was fed to the atomizer at 4°C. at a rate of 55 ml/min using a Watson Marlow peristaltic pump andsilicone tubing. The atomizer temperature control circulation jacket had4° C. water circulated through it. The atomizer air was flow controlledand measured using a needle valve and glass rotameter at 12 scfm and 42psig. Both air and liquid flows passed through polishing filters justprior to entering the atomizer (Millipak-60, and Millipore Wafergard IIF-40 In line Gas Filter). The drying air flow rate was controlled by anAC speed control system on the blower drive motor at 100 scfm and wasmeasured at the discharge of the blower using an orifice plate anddifferential pressure transducer. The drying air temperature wascontrolled at 145° C. on the Niro 7.5 KW heater. Particle collection wascarried out on a modified Pacific Engineering (Anaheim, Calif.)self-cleaning chamber (bag house or filter housing). The bag house wasbrought in house and modified to allow the number of filters to bevaried. Cage and fabric filters were replaced with two FaireyMicrofiltrex (Hampshire, UK) sintered metal fiber filter. A system forreverse pulsing (back flushing the bags with high pressure air) thefilter elements was built into the top of the bag house to aid inrecovery. The pulse was activated for less then one second every 20seconds. Pulse pressure was 110 psig. Powder dropped to the bottom ofthe bag house under gravity and mechanical aid (shaking). The powder inthe collector was analyzed as shown in Table 4.

TABLE 4 Attribute/Method Units Collector Moisture H₂O % wt. 4.8%  KarlFisher Particle size, MMD 1.34 μm Horiba Capa 700 % < 5 micron 100%  % <1.4 micron 62% % < 1.0 44% Delivered Dose Eff. % ± SD 73 ± 2 Dry Powderdevice

Although the foregoing invention has been described in some detail byway of illustration and example, for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

1. A composition comprising: a plurality of inhalable particles, eachcomprising insulin and a pharmaceutically acceptable carrier, whereinthe inhalable particles have a rugosity of at least 2, as determined byair permeametry and wherein the composition has an average particle sizeof less than 10 μm.
 2. The composition of claim 1, wherein the rugosityis at least
 3. 3. The composition of claim 1, wherein the rugosityranges from 2 to
 6. 4. The composition of claim 1, wherein the rugosityranges from 4 to
 6. 5. The composition of claim 1, wherein thepharmaceutically acceptable carrier comprises a buffer.
 6. Thecomposition of claim 5, wherein the buffer comprises sodium citrate. 7.The composition of claim 1, wherein the pharmaceutically acceptablecarrier comprises a penetration enhancer.
 8. The composition of claim 1,wherein the particles have a moisture content of less than 10 wt %. 9.The composition of claim 1, wherein the particles have a moisturecontent of less than 5 wt %.
 10. The composition of claim 1, wherein thecomposition has an average particle size of less than 5 μm.
 11. Thecomposition of claim 1, wherein the rugosity is at least 3, and whereinthe particles have a moisture content of less than 10 wt %.
 12. Thecomposition of claim 1, wherein the rugosity is at least 3, wherein thecomposition further comprises sodium citrate, and wherein the particleshave a moisture content of less than 10 wt %.
 13. The composition ofclaim 1, wherein the rugosity is at least 3, wherein the compositionfurther comprises a penetration enhancer, and wherein the particles havea moisture content of less than 10 wt %.
 14. A unit dosage, comprising atherapeutically effective amount of the composition of claim 1 within areceptacle.
 15. The unit dosage of claim 14, wherein the receptaclecomprises a capsule.
 16. The unit dosage of claim 14, wherein thereceptacle comprises a foil plastic laminate.
 17. A unit dosage,comprising between about 0.5 mg and 15 mg of the composition of claim 1within a receptacle.
 18. An inhalation device, wherein the receptacle ofclaim 14 is within the inhalation device.
 19. A composition comprising:a plurality of inhalable particles, each comprising insulin and apharmaceutically acceptable carrier, wherein the inhalable particleshave a rugosity of at least 2, as determined by BET, centrifugalsedimentary particle size analysis, and pycnometry, and wherein thecomposition has an average particle size of less than 10 μm.
 20. Thecomposition of claim 19, wherein the rugosity is at least
 3. 21. Thecomposition of claim 19, wherein the rugosity ranges from 2 to
 6. 22.The composition of claim 19, wherein the rugosity ranges from 4 to 6.23. The composition of claim 19, wherein the pharmaceutically acceptablecarrier comprises a buffer.
 24. The composition of claim 23, wherein thebuffer comprises sodium citrate.
 25. The composition of claim 19,wherein the pharmaceutically acceptable carrier comprises a penetrationenhancer.
 26. The composition of claim 19, wherein the particles have amoisture content of less than 10 wt %.
 27. The composition of claim 19,wherein the particles have a moisture content of less than 5 wt %. 28.The composition of claim 19, wherein the composition has an averageparticle size of less than 5 μm.
 29. The composition of claim 19,wherein the rugosity is at least 3, and wherein the particles have amoisture content of less than 10 wt %.
 30. The composition of claim 19,wherein the rugosity is at least 3, wherein the composition furthercomprises sodium citrate, and wherein the particles have a moisturecontent of less than 10 wt %.
 31. The composition of claim 19, whereinthe rugosity is at least 3, wherein the composition further comprises apenetration enhancer, and wherein the particles have a moisture contentof less than 10 wt %.
 32. A unit dosage, comprising a therapeuticallyeffective amount of the composition of claim 19 within a receptacle. 33.The unit dosage of claim 32, wherein the receptacle comprises a capsule.34. The unit dosage of claim 32, wherein the receptacle comprises a foilplastic laminate.
 35. A unit dosage, comprising between about 0.5 mg and15 mg of the composition of claim 19 within a receptacle.
 36. Aninhalation device, wherein the receptacle of claim 32 is within theinhalation device.
 37. A composition comprising a plurality of inhalableparticles, each comprising a drug and a pharmaceutically acceptablecarrier, wherein the inhalable particles have an average particle sizeof less than 10 μm and a rugosity of at least 3, as determined by BET,centrifugal sedimentary particle size analysis, and pycnometry.
 38. Thecomposition of claim 37, wherein the rugosity ranges from 4 to
 6. 39.The composition of claim 37, wherein the drug comprises a macromolecule.40. The composition of claim 39, wherein the macromolecule is selectedfrom proteins, polypeptides, oligopeptides, nucleic acids, andpolysaccharides.
 41. The composition of claim 39, wherein themacromolecule is selected from calcitonin, erythropoietin (EPO), factorIX, granulocyte colony stimulating factor, granulocyte macrophage colonystimulating factor, growth hormone, heparin, insulin, interferon alpha,interferon beta, interferon gamma, interleukin-2, leutenizing hormonereleasing hormone (LHRH), somatostatin analog, vasopressin analog,follicle stimulating hormone (FSH), amylin, ciliary neurotrophic factor,growth hormone releasing factor (GRF), insulin-like growth factor,insulinotropin, interferon beta, interferon gamma, interleukin-3,interleukin-4, interleukin-6, macrophage colony stimulating factor(M-CSF), nerve growth factor, parathyroid hormone, thymosin alpha 1,factor IIb/IIIa inhibitor, alpha-1 antitrypsin, anti-RSV antibody,cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease(DNase), bactericidal/permeability increasing protein (BPI), anti-CMVantibody, interleukin-1 receptor, and interleukin-1 receptor antagonist.42. The composition of claim 37, wherein the pharmaceutically acceptablecarrier comprises at least one member selected from carbohydrates, aminoacids, buffers, and salts.
 43. The composition of claim 42, wherein thepharmaceutically acceptable carrier comprises at least one memberselected from monosaccharides, disaccharides, polysaccharides, andhydrophobic amino acids.
 44. The composition of claim 42, wherein thepharmaceutically acceptable carrier comprises at least one memberselected from mannitol, trehalose, sodium chloride, sodium citrate,leucine, lactose, raffinose, alanine, and glycine.
 45. The compositionof claim 37, wherein the particles have a moisture content below 10 wt%.
 46. The composition of claim 37, wherein at least 90% by mass of theparticles have a size between 0.1 μm and 7 μm.
 47. The composition ofclaim 37, wherein at least 95% by mass of the particles have a sizebetween 0.4 μm and 5 μm.
 48. A composition comprising a plurality ofinhalable particles, each comprising insulin and a pharmaceuticallyacceptable carrier, wherein the inhalable particles have an averageparticle size of less than 10 μm and a rugosity of greater than 3, asdetermined by BET, centrifugal sedimentary particle size analysis, andpycnometry.
 49. The composition of claim 48, wherein the rugosity rangesfrom 4 to
 6. 50. The composition of claim 48, wherein thepharmaceutically acceptable carrier comprises at least one memberselected from carbohydrates, amino acids, buffers, and salts.
 51. Thecomposition of claim 50, wherein the pharmaceutically acceptable carriercomprises at least one member selected from monosaccharides,disaccharides, polysaccharides, and hydrophobic amino acids.
 52. Thecomposition of claim 50, wherein the pharmaceutically acceptable carriercomprises at least one member selected from mannitol, trehalose, sodiumchloride, sodium citrate, leucine, lactose, raffinose, alanine, andglycine.
 53. The composition of claim 48, wherein the particles have amoisture content below 10 wt %.
 54. The composition of claim 48, whereinat least 90% by mass of the particles have a size between 0.1 μm and 7μm.
 55. The composition of claim 48, wherein at least 95% by mass of theparticles have a size between 0.4 μm and 5 μm.
 56. A compositioncomprising: a plurality of inhalable particles having a rugosity of atleast 2, as determined by BET, centrifugal sedimentary particle sizeanalysis, and pycnometry, each of the plurality of inhalable particlescomprising: insulin; and a pH adjuster or buffer.
 57. The composition ofclaim 56, wherein the rugosity is at least
 3. 58. The composition ofclaim 56, wherein the rugosity ranges from 2 to
 6. 59. The compositionof claim 56, further comprising a pharmaceutically acceptable carrier.60. The composition of claim 59, wherein the pharmaceutically acceptablecarrier comprises one or more bulking agents.
 61. The composition ofclaim 60, wherein the one or more bulking agents comprises at least onemember selected from mannitol and glycine.
 62. The composition of claim61, wherein the pH adjuster or buffer comprises sodium citrate.
 63. Thecomposition of claim 56, wherein the particles have a moisture contentof less than 10 wt %.
 64. The composition of claim 56, wherein theparticles have a moisture content of less than 5 wt %.
 65. Thecomposition of claim 56, wherein the composition has an average particlesize of less than 10 μm.
 66. A composition comprising: a plurality ofinhalable particles, each comprising insulin and a pharmaceuticallyacceptable carrier, wherein the inhalable particles are made byatomizing a liquid medium comprising the insulin, the pharmaceuticallyacceptable carrier, and ethanol to form droplets, and drying thedroplets in a heated gas stream to produce the inhalable particles, andwherein the particles have a rugosity of at least 2, as determined byBET, centrifugal sedimentary particle size analysis, and pycnometry. 67.The composition of claim 66, wherein the rugosity is at least
 3. 68. Thecomposition of claim 66, wherein the rugosity ranges from 2 to
 6. 69.The composition of claim 66, wherein the pharmaceutically acceptablecarrier comprises a buffer.
 70. The composition of claim 69, wherein thebuffer comprises sodium citrate.
 71. The composition of claim 66,wherein the particles have a moisture content of less than 10 wt %. 72.The composition of claim 66, wherein the particles have a moisturecontent of less than 5 wt %.
 73. The composition of claim 66, whereinthe composition has an average particle size of less than 10 μm.
 74. Thecomposition of claim 66, wherein the composition has an average particlesize of less than 5 μm.
 75. The composition of claim 66, wherein thepharmaceutically acceptable carrier comprises sodium citrate, andwherein the particles have a moisture content of less than 10 wt %. 76.A method of treating diabetes, comprising: pulmonarily administering tothe alveolar regions of the lungs of a subject a therapeuticallyeffective amount of a composition comprising inhalable particles, eachcomprising insulin and a pharmaceutically acceptable carrier, whereinthe inhalable particles have a rugosity of at least 2, as determined byair permeametry.
 77. The method of claim 76, wherein the rugosity is atleast
 3. 78. The method of claim 76, wherein the rugosity ranges from 2to
 6. 79. The method of claim 76, wherein the rugosity ranges from 4 to6.
 80. The method of claim 76, wherein the pharmaceutically acceptablecarrier comprises a buffer.
 81. The method of claim 80, wherein thebuffer comprises sodium citrate.
 82. The method of claim 76, wherein thepharmaceutically acceptable carrier comprises a penetration enhancer.83. The method of claim 76, wherein the particles have a moisturecontent of less than 10 wt %.
 84. The method of claim 76, wherein theparticles have a moisture content of less than 5 wt %.
 85. The method ofclaim 76, wherein the composition has an average particle size of lessthan 10 μm.
 86. The method of claim 76, wherein the composition has anaverage particle size of less than 5 μm.
 87. The method of claim 76,wherein the rugosity is at least 3, and wherein the particles have amoisture content of less than 10 wt %.
 88. The method of claim 76,wherein the rugosity is at least 3, wherein the composition furthercomprises sodium citrate, and wherein the particles have a moisturecontent of less than 10 wt %.
 89. The method of claim 76, wherein therugosity is at least 3, wherein the composition further comprises apenetration enhancer, and wherein the particles have a moisture contentof less than 10 wt %.
 90. A method of treating diabetes, comprising:pulmonarily administering to the alveolar regions of the lungs of asubject a therapeutically effective amount of a composition comprisinginhalable particles, each comprising insulin and a pharmaceuticallyacceptable carrier, wherein the inhalable particles have a rugosity ofat least 2, as determined by BET, centrifugal sedimentary particle size,and pycnometry.
 91. The method of claim 90, wherein the rugosity is atleast
 3. 92. The method of claim 90, wherein the rugosity ranges from 2to
 6. 93. The method of claim 90, wherein the rugosity ranges from 4 to6.
 94. The method of claim 90, wherein the pharmaceutically acceptablecarrier comprises a buffer.
 95. The method of claim 94, wherein thebuffer comprises sodium citrate.
 96. The method of claim 90, wherein thepharmaceutically acceptable carrier comprises a penetration enhancer.97. The method of claim 90, wherein the particles have a moisturecontent of less than 10 wt %.
 98. The method of claim 90, wherein theparticles have a moisture content of less than 5 wt %.
 99. The method ofclaim 90, wherein the composition has an average particle size of lessthan 10 μm.
 100. The method of claim 90, wherein the composition has anaverage particle size of less than 5 μm.
 101. The method of claim 90,wherein the rugosity is at least 3, and wherein the particles have amoisture content of less than 10 wt %.
 102. The method of claim 90,wherein the rugosity is at least 3, wherein the composition furthercomprises sodium citrate, and wherein the particles have a moisturecontent of less than 10 wt %.
 103. The method of claim 90, wherein therugosity is at least 3, wherein the composition further comprises apenetration enhancer, and wherein the particles have a moisture contentof less than 10 wt %.
 104. A method of delivery of a composition to thelungs of a subject, the method comprising: administering by inhalation acomposition in aerosolized form, wherein the composition comprisesinhalable particles, each comprising a drug and a pharmaceuticallyacceptable carrier, and wherein the inhalable particles have an averageparticle size of 10 μm and a rugosity of greater than 3, as determinedby BET, centrifugal sedimentary particle size analysis, and pycnometry.105. A method of delivery of a composition to the lungs of a subject,the method comprising: administering by inhalation a composition inaerosolized form, wherein the composition comprises inhalable particles,each comprising insulin and a pharmaceutically acceptable carrier, andwherein the inhalable particles have a rugosity of at least 2, asdetermined by air permeametry, and wherein the composition has anaverage particle size of less than 10 μm.
 106. A method of delivery of acomposition to the lungs of a subject, the method comprising:administering by inhalation a composition in aerosolized form, whereinthe composition comprises inhalable particles, each comprising insulinand a pharmaceutically acceptable carrier, and wherein the inhalableparticles have a rugosity of at least 2, as determined by BET,centrifugal sedimentary particle size analysis, and pycnometry, andwherein the composition has an average particle size of less than 10 μm.